Multidrug-resistant (MDR) Plasmodium falciparum is partially responsible for the global resurgence of malaria. With the failing of many antimalarial drugs, most malaria-endemic countries have changed to artemisinin-based combination therapies (ACTs). Although ACT is highly effective, recent detection of reduced sensitivity in P. falciparum to artemisinins in several regions of Southeast Asia has raised great concerns. Although early resistance detection is essential for deterring and containing resistance, current detection of artemisinin resistance relies exclusively on clinical observations and in vitro drug assays. The lack of understanding of the exact mode of action and the mechanism of resistance for artemisinins makes resistance surveillance in areas of artemisinin deployment very difficult. To address this urgent problem, we have selected Thailand, China's Yunnan and Myanmar as our strategic sites to investigate artemisinin resistance. Southeast Asia has been the epicenter of drug resistant malaria parasites. The prevalence of MDR parasites, extensive deployment of artemisinins often as monotherapy, and the detection of reduced susceptibility to artemisinins among parasite populations suggest that artemisinin resistance is likely to arise in this region. In this study, we propose to 1) systematically sample P. falciparum clinical isolates and accurately determine their in vitro sensitivity to a panel of antimalarial drugs including artemisinins; 2) determine the correlations of artemisinin-resistance with polymorphisms in the genome using both candidate gene and genome-wide association study (GWAS) approaches; 3) validate promising mutations within candidate genes through allelic exchange experiments; and 4) develop molecular methods for detecting the mutation(s) responsible for artemisinin resistance and perform field surveillance of the resistance marker(s). The integration of a comprehensive sampling scheme, accurate in vitro drug assays and GWAS will provide essential information for elucidating the mechanism of artemisinin resistance, understanding how artemisinin resistance evolves, and facilitating the design of molecular methods to closely monitor resistance development in areas of ACT deployment.